Adrenergic Transmission Facilitates Extinction of Conditional Fear in Mice

Abstract

Extinction of classically conditioned fear, like its acquisition, is active learning, but little is known about its molecular mechanisms. We recently reported that temporal massing of conditional stimulus (CS) presentations improves extinction memory acquisition, and suggested that temporal spacing was less effective because individual CS exposures trigger two opposing processes: (1) fear extinction, which is favored by CS massing, and (2) fear incubation (increase), which is favored by spacing. We here report the effects of manipulating the adrenergic system during massed or spaced CS presentations in fear-conditioned mice. We administered yohimbine (5 mg/kg), an ␣ 2 -receptor antagonist, or propranolol (10 mg/kg), a ␤-receptor antagonist, systemically prior to CS presentation sessions and recorded both short-and long-term changes in conditional freezing. Yohimbine treatment facilitated extinction of both cue and context fear with massed protocols. When given before spaced CS presentations, propranolol led to a persistent incubation of cue fear, whereas yohimbine led to persistent extinction, compared with vehicle-treated animals, which showed no change in fear. These results suggest that norepinephrine positively modulates the formation of fear extinction memories in mice. They also provide clear evidence that spaced CS presentations trigger both fear-reducing (extinction) and fear-increasing (incubation) mechanisms.

Mechanisms of fear extinction

“…With spaced tone extinction training, yohimbine blunted the within-session 'incubation' effect whereas propranolol exaggerated it, and yohimbine facilitated later extinction retention whereas propranolol impaired it. Based on these data, together with their previous findings, Cain et al 268 concluded that nonreinforcement of a previously fear conditioned CS produces two competing tendencies, extinction and incubation of fear, and that one or the other of these can be made dominant by varying the extinction training protocol (massed vs spaced) and/or by modulating adrenergic neurotransmission (with yohimbine promoting extinction and propranolol promoting incubation).…”

“…267 Adrenergic involvement in extinction has been the topic of two recent studies, both of which employed Pavlovian fear conditioning in mice with freezing as a measure of conditioned fear. The first of these 268 reported modulation of extinction by pre-extinction training administration of the a2 autoreceptor antagonist yohimbine and the b-adrenoreceptor antagonist propranolol. This study follows from a previous report from this group suggesting that extinction, unlike acquisition, proceeds more readily with massed trials (6 s interstimulus interval or ISI) than with spaced trials (600 s ISI), even when total CS exposure is held constant.…”

“…Cain et al 268 used both massed and spaced extinction training protocols with a tone CS, and increasing amounts of exposure to a context CS, to examine the role of adrenergic neurotransmission in extinction and 'incubation' of fear. In a simple context extinction paradigm, systemic administration of yohimbine before extinction training facilitated both within-session extinction and later extinction retention whereas systemic administration of propranolol had no effect compared to saline-treated controls.…”

Pathways to change in one-session exposure with and without cognitive intervention: An exploratory study in spider phobia

“…One-session treatments of maximally three hours (Zlomke & Davis, 2008) were used. Treatment protocols for both formats were based on Öst (1989), with small adaptations based on recent research (Cain, Blouin, & Barad, 2004;Tsao & Craske, 2000;see Craske & Mystkowski, 2006, for an overview). The protocol mainly involved in vivo exposure, combined with modeling by the therapist.…”

Compound Stimulus Presentation and the Norepinephrine Reuptake Inhibitor Atomoxetine Enhance Long-Term Extinction of Cocaine-Seeking Behavior

“…Both behavioral and pharmacological treatments have been shown to improve extinction of conditioned fear or responding for food (Rescorla, 2000(Rescorla, , 2006Cain et al, 2004;Morris and Bouton, 2007;Janak and Corbit, 2010). Errorcorrection learning models argue that learning occurs when there is a discrepancy between what is expected, based on the presence of predictors, such as conditioned cues, and what actually occurs (reward, in appetitive conditioning; Kamin, 1968;Rescorla and Wagner, 1972;Schultz and Dickinson, 2000).…”